Effect of Prone Position on Ventilator-Induced Lung Injury

俯卧位对呼吸机所致肺损伤的影响

基本信息

批准号：
9251428
负责人：
Guido Musch
金额：
--
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2019-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9251428
关键词：
Effect Prone Position Ventilator Induced

项目摘要

Project Summary The incidence of acute lung injury (ALI) has been recently estimated at 86.2 per 100,000 person-years and its mortality rate at 38.5%. These figures imply that 74,500 persons die from ALI each year in the United States, a figure comparable to the deaths from breast cancer or HIV, and that 2.2 million Intensive Care Unit days and 3.6 million hospital days are devoted to the care of patients with ALI. Ventilator-induced lung injury (VILI) has been identified as a contributor to the morbidity and mortality from ALI. Although not yet conclusive, data from clinical trials suggest that prone positioning may improve survival in ALI. A possible reason for this improvement is reduction of VILI. Neutrophils have been shown to play a crucial role in the pathogenesis of VILI and we recently demonstrated that neutrophil metabolic activation occurs early during VILI. The broad, long-term objective of this research is to improve the understanding of mechanisms of VILI and to develop means to prevent or reduce it. To this end, the present grant proposal examines the overarching hypothesis that, by promoting uniform parenchymal aeration and tidal volume distribution throughout the lung, prone positioning leads to a reduction of neutrophil metabolic activation caused by large localized tidal expansion. This hypothesis will be examined in a large animal with physiology similar to the human (i.e., sheep), in three specific aims. Specific aim 1 examines the effectiveness of the prone position as a means to delay the onset and decrease the severity and topographical heterogeneity of VILI-induced neutrophil activation in initially uninjured lungs ventilated with large tidal volume. In specific aim 2, a well-characterized experimental model of ALI in which saline lung lavage leads to surfactant depletion and markedly heterogeneous loss of aeration is used to investigate whether the prone position leads to decreased neutrophil activation in dorsal lung regions, which are expected to regain aeration and more uniform tidal expansion as a result of the body position change. In specific aim 3, a graded increase in tidal volume is used to test the hypothesis that the prone position allows for higher tidal volumes than the supine position without augmenting neutrophil activation in a pre-injured lung. Positron Emission and Computed Tomography imaging and advanced tracer kinetic modeling will be employed to measure regional metabolic activity of neutrophils, pulmonary perfusion and aeration in vivo. It is expected that application of this integrated anatomic, physiologic and molecular imaging approach to the tightly knit specific aims will provide novel insights into the mechanism by which prone positioning may attenuate VILI. The direct clinical applicability of the methodological approach, the similarities in pulmonary physiology between sheep and humans and the use of a well-characterized model of ALI greatly enhance the translational aspect of this project. Consequently, the proposed studies will likely contribute to establishing if a strong rationale exists for the use of prone positioning in the ventilatory management of critically ill patients with ALI, and can be viewed as conducive to subsequent studies in patients.

项目摘要急性肺损伤（ALI）的发病率最近估计为每100,000人年86.2 死亡率为38.5％。这些数字暗示着每年有74,500人死于美国的阿里，一个数字与乳腺癌或艾滋病毒的死亡以及220万个重症监护病房的死亡相提并论和 360万医院的日子专门致力于对ALI患者的护理。呼吸机诱导的肺损伤（VILI）具有被确定为阿里发病率和死亡率的贡献者。尽管尚未结论，但来自临床试验表明，俯卧的定位可以提高ALI的生存率。可能的原因改善是Vili的减少。中性粒细胞已被证明在 Vili和我们最近证明了中性粒细胞代谢激活发生在VILI期间。广泛，这项研究的长期目标是提高对Vili机制的理解并发展意味着预防或减少它。为此，目前的赠款提案研究了总体假设通过促进整个肺部均匀的实质充气和潮汐体积分布，俯卧定位会导致大量局部潮汐扩张引起的中性粒细胞代谢激活的减少。该假设将在类似于人类（即绵羊）的大型动物中进行检查，在三个具体目标。特定目标1研究了俯卧位的有效性作为延迟发作的手段并减少Vili诱导的中性粒细胞激活的严重性和地形异质性未受伤的肺有大量潮汐体积。在特定的目标2中，一个良好的特征化实验模型盐水肺灌洗的ALI导致表面活性剂的耗竭和显着异质的曝气是用于研究俯卧位是否导致背肺区域中性粒细胞激活降低，由于身体位置，预计会恢复充气和更均匀的潮汐膨胀改变。在特定的目标3中，使用潮汐体积的分级增加来检验俯卧的假设与仰卧位相比，位置允许更高的潮汐体积，而无需增强中性粒细胞激活预伤的肺。正电子发射和计算机断层扫描成像和高级示踪动力学建模将用于测量中性粒细胞的区域代谢活性，肺部灌注和曝气体内。可以预期，这种综合的解剖，生理和分子成像方法的应用紧密编织的特定目的将为俯卧定位的机制提供新的见解衰减Vili。方法学方法的直接临床适用性，肺的相似性绵羊与人之间的生理学以及使用良好的Ali模型的使用极大地增强了这个项目的翻译方面。因此，拟议的研究可能有助于确定是否存在在重症患者的通风管理中使用俯卧的位置存在很强的理由使用ALI，可以看作是有利于患者的后续研究。